Ouachita Baptist University Scholarly Commons @ Ouachita

Honors Theses Carl Goodson Honors Program

2018

Dysregulation of Human Phase I Enzymes in APAP Overdose Subjects with Low ALT Levels

Aaron Woodall Ouachita Baptist University

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Part of the Pharmacy and Pharmaceutical Sciences Commons

Recommended Citation Woodall, Aaron, "Dysregulation of Human Phase I Enzymes in APAP Overdose Subjects with Low ALT Levels" (2018). Honors Theses. 655. https://scholarlycommons.obu.edu/honors_theses/655

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This Honors Thesis entitled

"Dysregulation of Human Phase I Enzymes in APAP Overdose Subjects with Low AL T Levels"

written by

Aaron Woodall

and submitted in partial fulfillment of the requirements for completion of the Carl Goodson Honors Program meets the criteria for acceptance and has been approved by the undersigned readers.

Dr. Jim Taylor, thesis director

Dr. Angela Douglass, second reader

Dr. Myra Houser, third reader

Dr. Barbara Pemberton, Honors Program director

April 20, 2018 Dysregulation of Human Phase I Enzymes in AP AP Overdose Subjects with Low AL T Levels Aaron Woodall

Background: Acetaminophen (APAP) is a common analgesic that can cause liver injury and death in high doses. Changes in gene expression following APAP overdose may be more sensitive indicators of liver injtrry than the current clinical indicator, alanine aminotransferase (ALT). The aim of this study was to examine gene expression of Phase I enzymes in pediatric AP AP overdose patients with low ALT levels (<75 lUlL), in order to understand the mechanism of APAP toxicity.

Methods: Blood samples were collected from control patients (no AP AP exposure; N=5) and APAP overdose patients {N=S). Using the P AXgene system, RNA was extracted from the blood samples and eDNA was synthesized. Quantitative polymerase chain reaction (qPCR) was performed and samples were profiled with an array containing 84 Phase I Enzyme drug metabolism genes. Results: The low ALT pediatric APAP overdose patients had higher (median [range]) ALT levels (35 [25,48] lUlL) compared to controls (16 [7, 20] IUIL). Three genes had significant downregulation that was later confirmed: GZMB (-2.86 fold, papoptosis, metabolism of valine and leucine (involved in the immune response), and hydroxylation of leukotriene B4 (involved in inflammation).

Conclusion: Dysregulation of Phase I Enzyme drug metabolism pathways has relevance for understanding mechanisms of cell injury in APAP toxicity. Pathway analysis points to the potential for a weakened immune response associated with AP AP overdose.

INTRODUCTION APAP toxicity does not have a clearly defined limit. Tylenol, the largest and most Acetaminophen (APAP) is a mild analgesic well-known distributer of APAP, recommends a found in many over-the-counter drugs. Taken in maximum daily dosage of 3,000 mg for adults. normal doses, it is generally regarded as safe For children, this amount greatly varies by and non-toxic, though liver injwy is common. weigh l and age [ I 0]. Nonetheless, the AP AP overdose is the leading cause of acute acetaminophen toxicity limit varies from person liver failure in the United States [6]. to person. Acetaminophen overdose is a common The clinical biomarker for APAP overdose is problem in the United States. A 2015 stu